Various drug delivery systems have been developed to lessen the toxicity and improve the efficacy of drugs. Anti-neoplastic and anti-cancer agents are of particular concern, due to the high cellular toxicity inherent in many of these drugs.
Ovarian Cancer is the fourth leading cause of death by cancer in women (ca. 15280 deaths in 2007 in the United States) (Greenlee, et al., Cancer Statistics, 2005. CA Cancer J Clin 2005; 51:15-36; Jemal, A., A. Thomas, T. Murray, and M. Thun, Cancer Statistics, 2002. CA: A Cancer Journal for Clinicians, 2002. 52: p. 23-47), the leading cause of death from gynecologic malignancies and the second most commonly diagnosed gynecologic malignancy. Ovarian cancer detection in the early stages is difficult because most women show little to no symptoms until the cancer has progressed to an advanced stage and become difficult to treat, with the relative survival rate at a low 46% (Greenlee et al., Cancer Statistics, 2005. CA Cancer J Clin 2005; 51:15-36; Schwartz P E, Taylor K J. Is early detection of ovarian cancer possible? Ann Med 1995; 27:519-28). Surgery is the first step in the treatment and is frequently necessary for diagnosis, as seen in FIG. 1. Chemotherapy is typically administered after surgery to treat any residual tumors. The traditional chemotherapeutic administration techniques include intravenous (IV) injection of the drugs directly into the blood stream (Armstrong, D. K., et al., Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New England Journal of Medicine, 2006. 354(1): p. 34-43; Markman, et al., Combination Intraperitoneal Chemotherapy with Cisplatin, Cytarabine, and Doxorubicin for Refractory Ovarian-Carcinoma and Other Malignancies Principally Confined to the Peritoneal-Cavity. J Clin Oncol, 1984. 2(12): p. 1321-1326). This technique has been used in the past years and has been successful in containing the spread of tumors and hence treating many types of cancer. Since it is not localized it exposes the whole body to the chemotherapy drugs. Hence, apart from destroying tumor cells they also attack normal healthy cells (Markman, et al., Combination Intraperitoneal Chemotherapy with Cisplatin, Cytarabine, and Doxorubicin for Refractory Ovarian-Carcinoma and Other Malignancies Principally Confined to the Peritoneal-Cavity. J Clin Oncol, 1984. 2(12): p. 1321-1326) resulting in extensive side effects.
Surgery is the first step in the treatment of cancerous tumors at early localized or intermediate stage, with chemotherapy used after surgery to treat any residual tumors. However, adjuvant chemotherapy suffers from non-specific distribution of drugs, and typically has severe side effects. Further, most chemotherapeutic drugs has low bioavailability, requiring multiple administrations, and therefore significantly increase the costs associated with treatment.
Conventional techniques to prevent cancer recurrence include intraperitonial chemotherapy. Drugs are delivered directly into the intraperitonial cavity (Armstrong, et al., Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New Eng J of Med, 2006. 354(1): p. 34-43) using a catheter, but also presents challenges. Tumors in the abdominal cavity are exposed to higher concentrations of drug for longer periods of time, resulting in increased hematologic, metabolic and neurologic toxicity (Armstrong, et al., Intraperitoneal cisplatin and paclitaxel in ovarian cancer. New Eng J of Med, 2006. 354(1): p. 34-43; Markman et al., Combination Intraperitoneal Chemotherapy with Cisplatin, Cytarabine, and Doxorubicin for Refractory Ovarian-Carcinoma and Other Malignancies Principally Confined to the Peritoneal-Cavity. Journal of Clinical Oncology, 1984. 2(12): p. 1321-1326; Hamilton &. Berek, Intraperitoneal chemotherapy for ovarian cancer. Curr Opinion in Oncol, 2006. 18(5): p. 507-515). Also, the catheters may become plugged over time (Hamilton & Berek, Intraperitoneal chemotherapy for ovarian cancer. Curr Opinion in Oncol, 2006. 18(5): p. 507-515) leading to infections and other complications. Moreover, this technique is available only to select patients with minimal residual tumors (Gore, et al., Intraperitoneal chemotherapy in ovarian cancer remains experimental. J Clin Oncol, 2006. 24(28): p. 4528-4530).
Localized delivery systems provide an alternative approach to chemotherapy, allowing for direct delivery to specific targeted sites. Moreover, localized delivery reduced toxicity as less drug is required, can be tailored to provide controlled and prolonged release of drug to the tumor or cancer cells, and reduced or eliminated the need for frequent administration of drug. Accordingly, local delivery provides low cost treatment, especially in comparison to traditional treatment.
Physical encapsulation or liposomes containing neutral or zwitterionic lipids have been used as localized drug delivery systems. The lipids in liposomes arrange themselves into bilayers and entrap one (unilameliar) or more (oligo- or multilamellar) spaces. The spaces between the bilayers of the lipids are usually filled with water. The liposome-encapsulated drugs are entrapped in the internal aqueous space. Conventional liposomes, which rely upon the internal entrapment of the drug, often have difficulty entrapping a high concentration of a drug, as the efficiency depends upon the volume of fluid outside of the liposomes and circumscribed within the internal aqueous vesicular space. During long-term storage, drugs entrapped within liposomes leak from the internal aqueous space into the surrounding milieu, causing the drug to be lost from its desired intra-liposomal location.
Accordingly, what is needed is an improved drug delivery system that allows progressive release of drug over a prolonged period of time.